The statements in this section merely provide background information related to the present disclosure and may not constitute prior art.
Allergy is a complex disease. Multiple immune cells and inflammatory mediators contribute to the initiation and manifestation of allergic diseases. In addition to the blockade of histamine H1 receptor, the anti-inflammatory effects have increasingly been recognized to play an important role in the management of allergic diseases. The anti-inflammatory effects include stabilization of mast cells (to prevent mediator release), blockade of lipid mediators such as platelet-activating factor (PAF) and leukotrienes, inhibition of adhesion molecules, and inhibition of eosinophils and CD4 T cells.
Allergic diseases have reached epidemic proportions worldwide. Allergic diseases such as asthma, rhinitis or atopic dermatitis affect at least 8%-16% population with the annual economic burden of 12.7, 1.2, and 3.8 billion dollars, respectively, in the United States and are a major health burden world-wide. The range of allergic diseases includes rhinitis, sinusitis, conjunctivitis, asthma, dermatitis and food allergy. These diseases negatively impact the patient's quality of life and impair their ability to perform in school or workplace. Thus, allergic diseases result in significant socio-economic costs.
Mast cells play a major role in allergy through secretion of granule associated and newly synthesized mediators. They are distributed widely in the body and are especially abundant in skin or mucosa where they can interact with foreign materials such as allergens or pathogens. Mast cells possess a large number of high affinity IgE receptors on their surface. Allergen binding to IgE receptors on mast cells initiates a cascade of signaling events leading to the production of potent inflammatory mediators including histamine, platelet-activating factor, IL-6 and many others.
The role of histamine in the pathophysiology of allergic disorders has been well-recognized. Mast cells produce and store histamine in their granules. Upon allergen activation, mast cells immediately (within seconds) release histamine into local tissues. Histamine exerts its effects in allergic diseases primarily through interacting with histamine H1 receptors which are present in a variety of organs such as nerve endings, blood vessel walls, and airway smooth muscles. Histamine has broad biological effects. Depending on the location where histamine is released, its biological effects vary from mild discomfort of itch to life-threatening bronchoconstriction. In the nose or skin, histamine induces vasodilation and increases vascular permeability leading to edema and erythema. It stimulates the sensory nerve endings leading to itching or sneezing. In the lung, histamine provokes the bronchial smooth muscle leading to bronchoconstriction.
H1 antihistamine agents play a pivotal role in the treatment of allergic diseases and are among the most prescribed medications in the world. Depending on their action on the central nervous system, H1 antihistamines are classified as first-generation and second-generation. In general, first-generation H1 antihistamines such as dexchlorpheniramine, hydroxyzine, contain two features that limit their usage. One, they are rapidly absorbed and metabolized. Thus, they need to be administered 3 to 4 times a day. Second, they are highly lipophilic and easily cross the blood-brain barrier causing a major side effect of sedation. Thus, major efforts have been made to improve H1 antihistamine agents by reducing their side effects on central nervous system and by enhancing the duration of drug effect.
Accordingly, there is a need for newer anti-allergy agents aimed at improved efficacy and reduced side effects.